Abstract
Background and objectives
Cervical cord atrophy is a key predictor of disability and disease progression in multiple sclerosis (MS); however, age-related vs disease-related contributions remain unclear. Here, we investigated whether MS results in a disease-specific reduction in mean upper cervical cord area (MUCCA) beyond aging, and whether this deviation is modulated by sex and age at disease onset.Methods
In this cross-sectional, multicenter study (3 Italian sites), we analyzed volumetric T1-weighted 3.0T brain MRIs and clinical data from healthy controls (HCs) and patients with MS (ages 18-70 years) without other cord pathology. Active-surface MUCCA measurements were obtained between C1 and C2/3 and normalized for head size (nMUCCA). nMUCCA lifespan trajectories were modelled in HC using polynomial regression accounting for age, age squared, sex, scanner, and interaction terms. Such model was applied to patients with MS generating nMUCCA Z-scores, capturing disease-specific atrophy beyond aging. Effects of sex and age at onset (pediatric onset Results
In HC (n = 480, median age 41.0 years, 59% female), nMUCCA showed a nonlinear age relationship, increasing until late 30s (p ≤ 0.033) and declining after age 50 years (p ≤ 0.008). Patients with MS (n = 1,295, median age 42.0 years, 68% female) showed cord Z-scores below zero from age 30 years (p ≤ 0.039), particularly in the fifth and sixth decades, indicating reductions vs HC. Slope analysis further revealed marked early-adult decline up to late 40s, with attenuation thereafter. These patterns did not differ between men and women. Pediatric-onset MS exhibited lower Z-scores (p p = 0.823) after disease duration adjustment. Disease-driven decline with age did not differ among onset groups (p = 0.668). Greater upper cervical cord atrophy correlated with higher disability and worse structural MRI measures (absolute ρ range = 0.196-0.392, all p Discussion
In MS, upper cord atrophy exceeds age-related effects, especially in fifth-sixth decades, and attenuates later as aging effects increase. Disease-specific atrophy is independent of sex. Differences across onset groups largely reflect disease duration. Upper cord atrophy correlates with disability, supporting its role as a sensitive MS-related neurodegeneration biomarker beyond aging.